The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors

Castelletti, Deborah; Fiaschetti, Giulio; Di Dato, Valeria; Ziegler, Urs; Kumps, Candy; De Preter, Katleen; Zollo, Massimo; Speleman, Frank; Shalaby, Tarek; De Martino, Daniela; Berg, Thorsten; Eggert, Angelika; Arcaro, Alexandre; Grotzer, Michael A (2010). The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors. Molecular cancer therapeutics, 9(12), pp. 3145-57. Philadelphia, Pa.: American Association for Cancer Research AACR 10.1158/1535-7163.MCT-10-0539

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The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G(1)/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Arcaro, Alexandre

ISSN:

1535-7163

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:13

Last Modified:

17 Mar 2015 19:15

Publisher DOI:

10.1158/1535-7163.MCT-10-0539

PubMed ID:

20889731

Web of Science ID:

000285296300005

URI:

https://boris.unibe.ch/id/eprint/2823 (FactScience: 205742)

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